Two mutations in mitochondrial ATP6 gene of ATP synthase, related to human cancer, affect ROS, calcium homeostasis and mitochondrial permeability transition in yeast.
The relevance of mitochondrial DNA (mtDNA) mutations in cancer process is still unknown. Since the mutagenesis of mitochondrial genome in mammals is not possible yet, we have exploited budding yeast S. cerevisiae as a model to study the effects of tumor-associated mutations in the mitochondrial MTATP6 gene, encoding subunit 6 of ATP synthase, on the energy metabolism. We previously reported that four mutations in this gene have a limited impact on the production of cellular energy. Here we show that two mutations, Atp6-P163S and Atp6-K90E (human MTATP6-P136S and MTATP6-K64E, found in prostate and thyroid cancer samples, respectively), increase sensitivity of yeast cells both to compounds inducing oxidative stress and to high concentrations of calcium ions in the medium, when Om45p, the component of porin complex in outer mitochondrial membrane (OM), was fused to GFP. In OM45-GFP background, these mutations affect the activation of yeast permeability transition pore (yPTP, also called YMUC, yeast mitochondrial unspecific channel) upon calcium induction. Moreover, we show that calcium addition to isolated mitochondria heavily induced the formation of ATP synthase dimers and oligomers, recently proposed to form the core of PTP, which was slower in the mutants. We show the genetic evidence for involvement of mitochondrial ATP synthase in calcium homeostasis and permeability transition in yeast. This paper is a first to show, although in yeast model organism, that mitochondrial ATP synthase mutations, which accumulate during carcinogenesis process, may be significant for cancer cell escape from apoptosis.


Late Middle Eocene primate from Myanmar and the initial anthropoid colonization of Africa.
Reconstructing the origin and early evolutionary history of anthropoid primates (monkeys, apes, and humans) is a current focus of paleoprimatology. Although earlier hypotheses frequently supported an African origin for anthropoids, recent discoveries of older and phylogenetically more basal fossils in China and Myanmar indicate that the group originated in Asia. Given the Oligocene-Recent history of African anthropoids, the colonization of Africa by early anthropoids hailing from Asia was a decisive event in primate evolution. However, the fossil record has so far failed to constrain the nature and timing of this pivotal event. Here we describe a fossil primate from the late middle Eocene Pondaung Formation of Myanmar, Afrasia djijidae gen. et sp. nov., that is remarkably similar to, yet dentally more primitive than, the roughly contemporaneous North African anthropoid Afrotarsius. Phylogenetic analysis suggests that Afrasia and Afrotarsius are sister taxa within a basal anthropoid clade designated as the infraorder Eosimiiformes. Current knowledge of eosimiiform relationships and their distribution through space and time suggests that members of this clade dispersed from Asia to Africa sometime during the middle Eocene, shortly before their first appearance in the African fossil record. Crown anthropoids and their nearest fossil relatives do not appear to be specially related to Afrotarsius, suggesting one or more additional episodes of dispersal from Asia to Africa. Hystricognathous rodents, anthracotheres, and possibly other Asian mammal groups seem to have colonized Africa at roughly the same time or shortly after anthropoids gained their first toehold there.


Healthcare costs of inflammatory myopathies.
Little information exists regarding the economic burden related to inflammatory myopathies. Our objective was to estimate health services costs in a large, unselected, population-based sample of patients with inflammatory myopathies. We identified subjects with polymyositis and dermatomyositis from administrative healthcare databases (covering all beneficiaries, about 7.5 million) in Quebec province, Canada. Average estimates of health services costs (physician visits, diagnostic tests and procedures, outpatient surgeries and procedures, acute care hospitalizations) for 2003 were calculated by multiplying health service use levels by the appropriate unit prices, determined from government fee schedules and other sources. Multiple linear regression analyses were performed to establish whether specific factors (age, sex, disease duration, region of residence, socioeconomic status, type of myositis, disease severity) were associated with cost. We identified 1102 subjects with inflammatory myopathy from January 1, 1989, to January 1, 2003. About two-thirds were women (68.9%); average age at case ascertainment was 57.4 years (SD 18.4). The average cost of all reimbursed health services, in 2008 Canadian dollars, was $4099 per patient (SD $9639). Costs increased with age, and were highest early in the disease course. Greater disease severity (defined as the need for prior hospitalization for myositis) was also a strong predictor of both physician costs and total costs. These results indicate significant economic burden related to inflammatory myopathies, with important demographic predictors. Our estimates suggest that the health services costs in inflammatory myopathies may equal, or exceed, those of other serious diseases, such as rheumatoid arthritis and systemic sclerosis.


Evaluation of the influence of arbitrary masks on the output field of optical systems using ABCD matrices.
We propose a method to express the complex field amplitude (CFA) at the output of any optical system with arbitrary masks. The method provides a general equation for any first-order optical system with given parameters and arbitrary masks. The method is based on the ABCD matrices of the system components, ignoring the masks. The obtained output CFA is formulated in a way that helps recognize the influence of each mask on the output CFA by projecting its influence on the output with the aid of ABCD matrices. The method offers a more transparent approach for efficient organization and minimization of the calculation steps.


Flooding and ecological restoration promote wetland microbial communities and soil functions on former cranberry farmland.
Microbial communities are early responders to wetland degradation, and instrumental players in the reversal of this degradation. However, our understanding of soil microbial community structure and function throughout wetland development remains incomplete. We conducted a survey across cranberry farms, young retired farms, old retired farms, flooded former farms, ecologically restored former farms, and natural reference wetlands with no history of cranberry farming. We investigated the relationship between the microbial community and soil characteristics that restoration intends to maximize, such as soil organic matter, cation exchange capacity and denitrification potential. Among the five treatments considered, flooded and restored sites had the highest prokaryote and microeukaryote community similarity to natural wetlands. In contrast, young retired sites had similar communities to farms, and old retired sites failed to develop wetland microbial communities or functions. Canonical analysis of principal coordinates revealed that soil variables, in particular potassium base saturation, sodium, and denitrification potential, explained 45% of the variation in prokaryote communities and 44% of the variation in microeukaryote communities, segregating soil samples into two clouds in ordination space: farm, old retired and young retired sites on one side and restored, flooded, and natural sites on the other. Heat trees revealed possible prokaryotic (Gemmatimonadetes) and microeukaryotic (Rhizaria) indicators of wetland development, along with a drop in the dominance of Nucletmycea in restored sites, a class that includes suspected mycorrhizal symbionts of the cranberry crop. Flooded sites showed the strongest evidence of wetland development, with triple the soil organic matter accumulation, double the cation exchange capacity, and seventy times the denitrification potential compared to farms. However, given that flooding does not promote any of the watershed or habitat benefits as ecological restoration, we suggest that flooding can be used to stimulate beneficial microbial communities and soil functions during the restoration waiting period, or when restoration is not an option.


An investigation on the use of data-driven scattering profiles in Monte Carlo simulations of ultraviolet light propagation in skin tissues.
Ultraviolet light can affect the appearance and medical condition of the human skin by triggering biophysical processes such as erythema, melanogenesis, photoaging and carcinogenesis. The evolution of these processes is related to the amount of ultraviolet light absorbed by skin pigments. This amount may vary with the wavelength and path length of the radiation that is propagated within the skin tissues. For many years, biomedical researchers have been investigating the propagation of ultraviolet light in skin tissues through Monte Carlo simulations. The scattering of the incident radiation by tissue internal structures, a key component in this process, is usually approximated by functions without a plausible connection with the underlying physical phenomena. In this paper, we examine the origins of such an approach, and question its generalized use with respect to wavelengths and biological materials for which there is no supporting data available. Furthermore, we perform comparisons to demonstrate that the accuracy and predictability of Monte Carlo simulations of ultraviolet propagation in skin tissues can be improved by using a data-driven approach to represent the scattering profile of these tissues.


Preparing a child with obstructive sleep apnea for transplantation.
All of the expected outcomes have been met for A.W. Intense collaboration among the pulmonary, nutrition, transplant, nephrology teams, and A.W.'s parents have accomplished what at first seemed to be quite difficult. After months of hard work and close monitoring of A.W., he was now at the 90th percentile on the growth curve. The diligence of the dietician and A.W.'s parents provided the intended outcome. A.W. had achieved a manageable weight and could be safely transplanted. The transplant team has decided to quickly taper prednisone until A.W. is completely off of this immunosuppressive after transplantation. A.W. is more cooperative with the nasal cannula at night and it is felt he will cooperate with the CPAP mask during the post-operative period in the hospital. He would need continued evaluation of his obstructive sleep apnea due to the potential of increased weight with immunosuppression medicines. All of A.W.'s blood culture results have been negative and his left tympanic membrane has not drained nor is there evidence of infection. A.W. is finally ready for transplantation. A date was set and A.W. and his living related donor were ready to proceed.


Development of a nanoparticulate formulation of retinoic acid that suppresses Th17 cells and upregulates regulatory T cells.
Retinoic acid (RA) is a small molecule capable of shunting developing T cells away from the Th17 lineage and towards the Treg phenotype, making it a potentially useful therapeutic for autoimmune and inflammatory diseases. However, therapy can be complicated by systemic toxicity and unpredictable bioavailability, making a targeted drug delivery vehicle for local therapy desirable. A promising approach is the use of nanoparticles, which have been demonstrated to increase potency and decrease toxicity of therapies in a variety of disease models including Th17 mediated diseases. Nanoparticles can also be targeted to specific cell types via surface modification, further increasing the potential specificity of this approach. We therefore constructed a nanoparticulate drug delivery platform from poly(lactic-co-glycolic acid) (PLGA) capable of encapsulating and releasing RA. Here we report the fabrication, characterization, and in vitro bioactivity of this platform. We demonstrate that RA containing PLGA nanoparticles suppress IL-17 production and ROR-γ(t) expression in T cells polarized towards the Th17 phenotype in vitro with similar potency to that of free drug. Furthermore, we show that these particles enhance TGF-β dependent Foxp3 expression and IL-10 production of T cells in vitro with similar potency to free RA. Finally, we demonstrate that T cells polarized towards the Th17 phenotype in the presence of free and nanoparticulate RA have similarly suppressed ability to induce IL-6 production by fibroblasts. Our findings demonstrate the feasibility of RA delivery via biodegradable nanoparticles and represent an exciting technology for the treatment of autoimmune and inflammatory diseases.


Emotional reactions of expectant fathers to their wives' first pregnancy.
A group of 51 expectant fathers, whose wives were in the last three months of their first pregnancy, was compared to a control group of 51 married men without children. On the Anxiety Scale Questionnaire the expectant fathers were significantly higher in overall anxiety (both overt and covert), as well as in tension and apprehensiveness. The Blacky Picture Test indicated stronger Oedipal intensity, sibling rivalry and guilt feelings in the experimental group than in the control group. Clinical interviews with six of the subjects revealed considerable ambivalence, frequently related to re-aroused infantile fantasies, feminine identifications, castration fears and Oedipal themes, as well as attempt to defend against the ambivalent feelings through negation, denial, isolation, repression, intellectualization and reaction formation. While the higher levels of anxiety could be understood as a reaction to a reality stress situation, the Blacky Test results and the interview material point to more specific dynamic factors, and support several psychoanalytic hypothesis about significance of pregnancy for the prospective father. The inner conflict aroused contributes to the intensified anxiety, which is likely to be overdetermined.


Neurobehavioral toxicology of the organoleads.
Alkyl leads (R x Pb) are environmentally prevalent compounds which have been shown to produce a variety of neurological and behavioral deficits in both laboratory animals and man. Due to the increasing commercial use of these compounds, the episodes of human poisoning, and the limited understanding of their sites and mechanisms of toxicity, the organoleads, as a class, remain potentially important environmental health hazards. Recent data indicate that the constellation of behavioral effects produced by these compounds resembles the behavioral sequelae of limbic system damage. For example, alterations in sensory responsiveness and/or behavioral reactivity and task-dependent changes in avoidance learning are observed following organolead exposure and experimental disruption of the limbic system. Furthermore, neurochemical changes induced by organoleads are regionally-specific and restricted to the limbic forebrain and frontal cortex. The present review will summarize the toxic properties of organoleads, discuss their neurobehavioral effects, and suggest that these effects might be attributable to a disruption of the limbic forebrain.


JunB-CBFbeta signaling is essential to maintain sarcomeric Z-disc structure and when defective leads to heart failure.
In muscle cells, a complex network of Z-disc proteins allows proper reception, transduction and transmission of mechanical and biochemical signals. Mutations in genes encoding different Z-disc proteins such as integrin-linked kinase (ILK) and nexilin have recently been shown to cause heart failure by distinct mechanisms such as disturbed mechanosensing, altered mechanotransduction or mechanical Z-disc destabilization. We identified core-binding factor β (CBFβ) as an essential component for maintaining sarcomeric Z-disc and myofilament organization in heart and skeletal muscle. In CBFβ-deficient cardiomyocytes and skeletal-muscle cells, myofilaments are thinned and Z-discs are misaligned, leading to progressive impairment of heart and skeletal-muscle function. Transcription of the gene encoding CBFβ mainly depends on JunB activity. In JunB-morphant zebrafish, which show a heart-failure phenotype similar to that of CBFβ-deficient zebrafish, transcript and protein levels of CBFβ are severely reduced. Accordingly, ectopic expression of CBFβ can reconstitute cardiomyocyte function and rescue heart failure in JunB morphants, demonstrating for the first time an essential role of JunB-CBFβ signaling for maintaining sarcomere architecture and function.


[Cardiohemodynamic features and character of depressive disorders in patients with anemia varying grades of severity with chronic heart failure and chronic kidney disease].
Anemia and renal dysfunction are considered as predictors of an unfavorable course of chronic heart failure, the presence of depressive disorders in these patients is a risk factor for recurrent hospitalizations and deaths. The aim--study of morphological and functional changes in the myocardium, as well as the assessment of the existence and character of depressive disorders in patients with anemia varying grades of severity, developed on a background of chronic heart failure and chronic kidney disease. Structural and functional parameters of myocardium were investigated by echocardioscopy. Beck Depression Inventory was used to assess the presence and character of depressive disorders. The progression of anemic syndrome was accompanied by dilation of the left and right cavities of heart, inotropic function decreasing. In patients with anemic syndrome on a base of chronic heart failure and chronic kidney disease depressive disorders are observed mainly due to the cognitive-affective disorders in 1st grade anemia, and their combination with somatic manifestations of depression in patients with anemia of 2d and 3d grade.


Modification of Na and Cl transport in canine tracheal mucosa by prostaglandins.
We tested the effect of prostaglandins PGF2 alpha and PGE1 on the transport of 36Cl and 22Na by canine tracheal epithelium. Sheets of epithelium were mounted in Ussing chambers and short-circuited. Addition of PGF2 alpha to the mucosal side resulted in an increase of net Cl secretion from 0.71 +/- 0.41 to 2.40 +/- 0.67 mu eq . cm-2 . h-1 without significant effect on net Na absorption. Prostaglandin E1 on the mucosal side increased net Cl secretion from 1.36 +/- 0.31 to 2.69 +/- 0.35 and decreased Na absorption from 0.87 +/- 0.16 to 0.49 +/- 0.09. Indomethacin significantly depressed net Cl secretion from 1.36 +/- 0.36 to 0.57 +/- 0.22. Subsequent addition of PGE1 augmented net Cl secretion to 3.88 +/- 0.75. PGE1 did not enhance [14C]mannitol fluxes across this epithelium. Cellular levels of cAMP increased in response to PGE1 from 130 +/- 12.7 to 642 +/- 33.4 pmol . mg prot-1 . 10 min-1, whereas PGF2 alpha had no effect. These data suggest that although effects of PGF2 alpha and PGE1 are similar as pertains to net Cl secretion, they differ in their effects on Na transport and their capacity to increase cAMP levels. Alterations in Cl and Na transport in response to PGE1 are likely to be mediated, at least in part, by the adenylate cyclase-cAMP system. Furthermore, endogenous prostaglandins may have an important regulatory role in ion transport by airways epithelium.


Patient-reported complications after cryoablation therapy for prostate cancer.
To define the patient-reported complications after cryoablation therapy for prostate cancer and to compare these results to previously published patient-reported complications for radical prostatectomy and external beam irradiation. A questionnaire similar to previously published patient-reported complication studies was sent to the first 290 patients treated by cryoablation therapy at our Institution. The questionnaire was returned by 267 patients. Forty-four patients were excluded from analysis because of prior irradiation, transurethral prostatectomy, or cryoablation, resulting in a study group of 223 patients. Of the 208 patients with good urinary control preoperatively, 9 (4.3%) patients used incontinence pads after cryoablation. Seven of the 8 patients who used one pad daily reported leakage of only a few drops. Impotency, defined as an inability to obtain erections adequate for vaginal penetration, occurred in 85% of men who were potent preoperatively. Urethrorectal fistula occurred in 1 patient (0.4%). Bladder outlet obstruction caused by stricture of sloughed necrotic prostatic tissue required dilation or transurethral resection in 10% of patients. Scrotal swelling, penile tingling, and pelvic pain occurred in 18, 15, and 12% of patients, respectively; typically, these resolved spontaneously within 3 months. Patient-reported complications for cryoblation compared favorably to those reported for radical prostatectomy and external beam irradiation. Patient satisfaction was high; 96% of patients reported that they would choose cryosurgery as a treatment option again.


Oppression and exposure as differentiating predictors of types of workplace violence for nurses.
To extend a model of the antecedents of workplace bullying to apply to a wider range of types of workplace aggression, including bullying and several types of violence, among nurses. Research that has focused on workplace bullying has found that the Demand-Control-Support model, negative affectivity and certain demographic factors play important roles as antecedents of bullying. A cross-sectional design. A validated questionnaire was sent to the work addresses of all nursing and midwifery staff in a medium-to-large hospital in Australia. A total of 273 nurses and midwives returned their completed questionnaires. Ordinal regressions were conducted to assess the antecedents of workplace aggression across bullying and violence. Aspects of the Demand-Control-Support model and job tenure significantly predicted particular forms of violence, while negative affectivity and work schedule were significant for bullying. The patterns of the results suggest key mechanisms that characterise certain forms of violence and distinguish between bullying and types of violence across the range of workplace aggression. In particular, oppression and exposure appear to differentiate types of workplace violence. The study suggests ways in which nursing and hospital managers may act to reduce the likelihood of certain forms of aggression, particularly violence, from occurring.


Biochemical Implications of Biotransformation of Some Toxic Floras Using Natural Local Enzyme Sources.
Recently, it has been established that simultaneous saccharification and fermentation is a potent technique for the detoxification of harmful plant materials. Following encouraging simultaneous medicinal applications of snail slime and yeast, we exploited their hydrolytic and fermentation potentials to prevent toxicities of the selected floras; Erythrodontium barteri (EB), bracken fern (BF), and crustose lichens (CL). The applicability of the saccharification process has been described in a patent (WO2005010193A2). The plants were bioprocessed using snail digestive juice and yeast slurry and their health effects were evaluated. Seventy rats were divided equally into groups, treated with single doses of aqueous extracts of the plants and their bioprocessed forms, and compared with control rats. The plants showed very high antinutrients levels, which significantly reduced after SSF with enhanced flavonoids, alkaloids and phenols. Potential alterations of WBC differentials, RBC, liver and renal function markers indices were mitigated by bioprocessed extracts. MDA, SOD, GRase, XO and XDH levels in rats administered the bEB and CL were equivalent to the levels found for the control rats. Some bioprocessed plants produced unaltered insulin, ghrelin, and leptin levels. The bioprocessed extracts, when compared to the effects of unprocessed extracts, produced lower TNF-α, Caspase-3, and adiponectin levels and mitigated the potential suppression of Na+/K+-ATPase levels. Potential depletion of inhibin-B, testosterone, estrogen, and prolactin was mitigated after bioprocessing. This study, thus, validates the application of bioprocessing using snail digestive juice and yeast as an effective approach to reduce the potential toxicities of harmful plants.


Gene expression profiling of porcine alveolar macrophages after antibody-mediated cross-linking of Sialoadhesin (Sn, Siglec-1).
Sialoadhesin (Sn) is the prototypic member of the Siglecs, a family of receptors mainly involved in cell-cell interactions. For several Siglecs, but not for Sn, intracellular signaling functions have been described. Because antibody-mediated cross-linking of surface transmembrane proteins is a powerful technique to investigate cell-molecular events, Sn expressed on porcine alveolar macrophages (PAM) was cross-linked with the antibody 41D3, and the expression profiles were compared with mock-treated macrophages by microarray analysis. Gene ontology analysis of 479 differentially expressed transcripts identified gene categories related to membrane localization, signal transduction, receptor and communication activities. Analyses of the human KEGG pathway database identified MAP kinase signaling, regulation of actin cytoskeleton, adipocytokine signaling, and wnt signaling as significantly altered pathways, supporting a role for Sn as intracellular signaling molecule. Real-time PCR of a subset of modulated genes confirmed these results and highlighted the reliability of a short-term cross-linking treatment for transcriptomic analysis of receptor functions.


Sintered S53P4 bioactive glass scaffolds have anti-inflammatory properties and stimulate osteogenesis in vitro
Bioactive glasses (BAG) are used as bone-graft substitutes in orthopaedic surgery. A specific BAG scaffold was developed by sintering BAG-S53P4 granules. It is hypothesised that this scaffold can be used as a bone substitute to fill bone defects and induce a bioactive membrane (IM) around the defect site. Beyond providing the scaffold increased mechanical strength, that the initial inflammatory reaction and subsequent IM formation can be enhanced by coating the scaffolds with poly(DL-lactide-co-glycolide) (PLGA) is also hypothesised. To study the immunomodulatory effects, BAG-S53P4 (± PLGA) scaffolds were placed on monolayers of primary human macrophage cultures and the production of various pro- and anti-inflammatory cytokines was assessed using reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) and ELISA. To study the osteogenic effects, BAG-S53P4 (± PLGA) scaffolds were cultured with rabbit mesenchymal stem cells and osteogenic differentiation was evaluated by RT-qPCR and matrix mineralisation assays. The scaffold ion release was quantified and the BAG surface reactivity visualised. Furthermore, the pH of culture media was measured. BAG-S53P4 scaffolds had both anti-inflammatory and osteogenic properties that were likely attributable to alkalinisation of the media and ion release from the scaffold. pH change, ion release, and immunomodulatory properties of the scaffold could be modulated by the PLGA coating. Contrary to the hypothesis, the coating functioned by attenuating the BAG surface reactions and subsequent anti-inflammatory properties, rather than inducing an elevated inflammatory response compared to BAG-S53P4 alone. These results further validated the use of BAG-S53P4 (± PLGA) scaffolds as bone substitutes and indicate that scaffold properties can be tailored to a specific clinical need.


Listeria cerebritis: relapse of infection in renal transplant patients.
In 3 cases of Listeria cerebritis, two of the patients had relapse with cerebritis after antimicrobial therapy for acute Listeria septicemia or meningitis. Each had received ten to 14 days of intravenous penicillin. Relapse occurred with fever and sudden focal cerebral dysfunction. Brain scans showed focal uptake; arteriograms and computerized tomography were normal. Cerebrospinal fluids were nondiagnostic; blood cultures yielded Listeria in two patients. Penicillin treatment for six weeks produced rapid clinical responses that were complete in one and minimal residual in two. Progress brain scans were normal. A relapse rate of 35% is reported in transplant patients with Listeria meningitis and/or bacteremia who are treated for less than three weeks; to our knowledge, cerebritis in such patients has not been reported previously. High-dose penicillin or ampicillin therapy for four to six weeks is recommended for Listeria infections in this select group.


Combined flow cytometry determination of S-phase fraction and DNA ploidy is an independent prognostic factor in node-negative invasive breast carcinoma: analysis of a series of 271 patients with stage I and II breast cancer.
To assess the significance of S-phase fraction (SPF) and DNA ploidy evaluated by DNA flow cytometry as prognostic markers in stage I or II breast cancer. A series of 271 patients, treated by surgery, radiotherapy +/- systemic therapy was analyzed (median follow up: 64 months). Standardized flow cytometry cell preparation from frozen samples and consensus rules for data interpretation were followed. Three SPF classes were defined on the basis of tertiles after adjustment for ploidy. Four groups were defined based on combinations of DNA ploidy (DIP: diploid; ANEUP: aneuploid) and SPF: DIP and low SPF (DL, n=37), DIP and medium or high SPF (DMH, n=76), ANEUP and low SPF (AL, n=24), ANEUP and medium or high SPF (AMH, n=68). Local control rate (LCR), disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS) were correlated with DNA ploidy, SPF, DL to AMH groups, T and N stages, SBR grading, age, and hormonal status on univariate and multivariate analysis (Cox model). On univariate analysis, DFS and LCR were higher for DIP tumours. High SPF values were associated with shorter DFS. LCR, MFS, DFS, and OS rates were significantly different with an increasingly poorer prognosis from DL to AMH. On multivariate analysis, groups DL to AMH, histological node involvement and T stage were independently associated with MFS, and DFS. In N- patients, DL to AMH remained independent for MFS and DFS. For SBR III tumours, MFS and OS were significantly different in DL to AMH groups. These results strongly support the use of combined evaluation of DNA ploidy and SPF as independent parameters in clinical trials for N- stage I and II breast cancer.


Nuclear progestin receptor (pgr) knockouts in zebrafish demonstrate role for pgr in ovulation but not in rapid non-genomic steroid mediated meiosis resumption.
Progestins, progesterone derivatives, are the most critical signaling steroid for initiating final oocyte maturation (FOM) and ovulation, in order to advance fully-grown immature oocytes to become fertilizable eggs in basal vertebrates. It is well-established that progestin induces FOM at least partly through a membrane receptor and a non-genomic steroid signaling process, which precedes progestin triggered ovulation that is mediated through a nuclear progestin receptor (Pgr) and genomic signaling pathway. To determine whether Pgr plays a role in a non-genomic signaling mechanism during FOM, we knocked out Pgr in zebrafish using transcription activator-like effector nucleases (TALENs) and studied the oocyte maturation phenotypes of Pgr knockouts (Pgr-KOs). Three TALENs-induced mutant lines with different frame shift mutations were generated. Homozygous Pgr-KO female fish were all infertile while no fertility effects were evident in homozygous Pgr-KO males. Oocytes developed and underwent FOM normally in vivo in homozygous Pgr-KO female compared to the wild-type controls, but these mature oocytes were trapped within the follicular cells and failed to ovulate from the ovaries. These oocytes also underwent normal germinal vesicle breakdown (GVBD) and FOM in vitro, but failed to ovulate even after treatment with human chronic gonadotropin (HCG) or progestin (17α,20β-dihydroxyprogesterone or DHP), which typically induce FOM and ovulation in wild-type oocytes. The results indicate that anovulation and infertility in homozygous Pgr-KO female fish was, at least in part, due to a lack of functional Pgr-mediated genomic progestin signaling in the follicular cells adjacent to the oocytes. Our study of Pgr-KO supports previous results that demonstrate a role for Pgr in steroid-dependent genomic signaling pathways leading to ovulation, and the first convincing evidence that Pgr is not essential for initiating non-genomic progestin signaling and triggering of meiosis resumption.


Phaeohyphomycosis due to Exophiala in Aquarium-Housed Lumpfish (Cyclopterus lumpus): Clinical Diagnosis and Description.
Phaeohyphomycosis caused by Exophiala species represents an important disease of concern for farmed and aquarium-housed fish. The objective of this study was to summarize the clinical findings and diagnosis of Exophiala infections in aquarium-housed Cyclopterus lumpus. Clinical records and postmortem pathology reports were reviewed for 15 individuals from 5 public aquaria in the United States and Canada from 2007 to 2015. Fish most commonly presented with cutaneous ulcers and progressive clinical decline despite topical or systemic antifungal therapy. Antemortem fungal culture of cutaneous lesions resulted in colonial growth for 7/12 samples from 8 individuals. Amplification of the internal transcribed spacer region (ITS) of nuclear rDNA identified Exophiala angulospora or Exophiala aquamarina in four samples from three individuals. Postmortem histopathologic findings were consistent with phaeohyphomycosis, with lesions most commonly found in the integument (11/15), gill (9/15), or kidney (9/15) and evidence of fungal angioinvasion and dissemination. DNA extraction and subsequent ITS sequencing from formalin-fixed paraffin-embedded tissues of seven individuals identified E. angulospora, E. aquamarina, or Cyphellophora sp. in four individuals. Lesion description, distribution, and Exophiala spp. identifications were similar to those reported in farmed C. lumpus. Antemortem clinical and diagnostic findings of phaeohyphomycosis attributable to several species of Exophiala provide insight on the progression of Exophiala infections in lumpfish that may contribute to management of the species in public aquaria and under culture conditions.


Efficacy of sublingual specific immunotherapy on allergic asthma and rhinitis in children's real life.
Sublingual-specific immunotherapy (SLIT) is considered as a valid treatment of respiratory allergies. We performed a case-control study to evaluate the effect of SLIT in children with allergic asthma and rhinitis. The study plan included 140 patients (age 6-14 yr, 43% girls and 57% boys) presenting allergic rhinitis and/or asthma, 70 treated with SLIT actively for three years and 70 controls never treated with specific immunotherapy (only symptomatic drugs). Rhinitis Symptom Score (RSS), Asthma Symptom Score (ASS) and Medication Score (MS) were evaluated at beginning and during the 3 years of immunotherapy. results: There was a significant improvement of RSS (mean ± SD) in the SLIT group: baseline 5.31 ± 2.01, third year 1.38 ± 1.06 (p < 0.0001 vs baseline). baseline 5.00 ± 1.08, third year 4.68 ± 1.152 (P ¼ NS). ASS (mean ± SD) in the SLIT group: baseline 4.09 ± 2.21, third year 1.23 ± 1.4 (p < 0.0001 vs baseline). baseline 4.04 ± 2.46, third year 3.62 ± 2.26 (p ¼ NS). MS (mean ± SD) in the SLIT group: baseline 3.30 ± 1.4, third year 0.88 ± 1.26 (p < 0.0001 vs baseline). baseline 3.19 ± 1.23, third year 3.39 ± 1.12 (p ¼ NS). There are no statistically significant differences among monosensitized/polysensitized patients and at different age ranges. None of the patients included reported severe systemic reactions or anaphylaxis. During the treatment, the active group showed sustained reductions in mean asthma and rhinitis symptom scores when compared with controls to confirm the efficacy and safety of sublingual immunotherapy.


Visual signalling by asymmetry: a review of perceptual processes.
Individual levels of asymmetry in traits that display fluctuating asymmetry could be used as visual signals of phenotypic (and perhaps genotypic) quality, as asymmetry can often be negatively related to fitness parameters. There are some data to support this hypothesis but the experimental protocols employed have commonly resulted in asymmetries far larger than those observed in nature. To date, there has been little consideration of the ability of animals to accurately discriminate small asymmetries (of the magnitude observed in the wild) from perfect symmetry. This is key to assessing the plausibility of the asymmetry-signalling hypothesis. Here, I review the perceptual processes that may lead to the discrimination of asymmetry and discuss a number of ecologically relevant factors that may influence asymmetry signalling. These include: signal orientation, distance of trait elements from the axis of symmetry, trait complexity, trait contrast and colour, and the behaviour of both signaller and receiver. I also discuss the evolution of symmetry preferences and make suggestions as to where researchers should focus attention to examine the generality of asymmetry-signalling theory. In highly developmentally stable signalling systems the magnitude of asymmetry may be too small to be detected accurately and reliably, hence asymmetry signalling is unlikely to have evolved in these situations.


Single adult human CD34(+)/Lin-/CD38(-) progenitors give rise to natural killer cells, B-lineage cells, dendritic cells, and myeloid cells.
Marrow stromal cultures support adult CD34(+)/Lin-/HLA-DR- or CD34(+)/Lin-/CD38(-) cell differentiation into natural killer (NK) or myeloid cells, but unlike committed lymphoid progenitors (CD34(+)/Lin-/CD45RA+/CD10(+)), no B cells are generated. We tested whether different microenvironments could establish a developmental link between the NK and B-cell lineages. Progenitors were cultured in limiting dilutions with interleukin-7 (IL-7), flt3 ligand (FL), c-kit ligand (KL), IL-3, IL-2, and AFT024, a murine fetal liver line, which supports culture of transplantable murine stem cells. NK cells, CD10(+)/CD19(+) B-lineage cells and dendritic cells (DC) developed from the same starting population and IL-7, FL, and KL were required in this process. Single cell deposition of 3,872 CD34(+)/Lin-/CD38(-) cells onto AFT024 with IL-7, FL, KL, IL-2, and IL-3 showed that a one time addition of IL-3 at culture initiation was essential for multilineage differentiation from single cells. Single and double lineage progeny were frequently detected, but more importantly, 2% of single cells could give rise to at least three lineages (NK cells, B-lineage cells, and DC or myeloid cells) providing direct evidence that NK and B-lineage differentiation derive from a common lymphomyeloid hematopoietic progenitor under the same conditions. This study provides new insights into the role of the microenvironment niche, which governs the earliest events in lymphoid development.


Effects of Avatar Perspective on Joint Excursions Used to Play Virtual Dodgeball: Within-Subject Comparative Study.
Visual representation of oneself is likely to affect movement patterns. Prior work in virtual dodgeball showed greater excursion of the ankles, knees, hips, spine, and shoulder occurs when presented in the first-person perspective compared to the third-person perspective. However, the mode of presentation differed between the two conditions such that a head-mounted display was used to present the avatar in the first-person perspective, but a 3D television (3DTV) display was used to present the avatar in the third-person. Thus, it is unknown whether changes in joint excursions are driven by the visual display (head-mounted display versus 3DTV) or avatar perspective during virtual gameplay. This study aimed to determine the influence of avatar perspective on joint excursion in healthy individuals playing virtual dodgeball using a head-mounted display. Participants (n=29, 15 male, 14 female) performed full-body movements to intercept launched virtual targets presented in a game of virtual dodgeball using a head-mounted display. Two avatar perspectives were compared during each session of gameplay. A first-person perspective was created by placing the center of the displayed content at the bridge of the participant's nose, while a third-person perspective was created by placing the camera view at the participant's eye level but set 1 m behind the participant avatar. During gameplay, virtual dodgeballs were launched at a consistent velocity of 30 m/s to one of nine locations determined by a combination of three different intended impact heights and three different directions (left, center, or right) based on subject anthropometrics. Joint kinematics and angular excursions of the ankles, knees, hips, lumbar spine, elbows, and shoulders were assessed. The change in joint excursions from initial posture to the interception of the virtual dodgeball were averaged across trials. Separate repeated-measures ANOVAs revealed greater excursions of the ankle (P=.010), knee (P=.001), hip (P=.0014), spine (P=.001), and shoulder (P=.001) joints while playing virtual dodgeball in the first versus third-person perspective. Aligning with the expectations, there was a significant effect of impact height on joint excursions. As clinicians develop treatment strategies in virtual reality to shape motion in orthopedic populations, it is important to be aware that changes in avatar perspective can significantly influence motor behavior. These data are important for the development of virtual reality assessment and treatment tools that are becoming increasingly practical for home and clinic-based rehabilitation.


Gut permeability and mucosal inflammation: bad, good or context dependent.
Inflammatory bowel disease (IBD) is a multifactorial disease. A breach in the mucosal barrier, otherwise known as "leaky gut," is alleged to promote mucosal inflammation by intensifying immune activation. However, interaction between the luminal antigen and mucosal immune system is necessary to maintain mucosal homeostasis. Furthermore, manipulations leading to deregulated gut permeability have resulted in susceptibility in mice to colitis as well as to creating adaptive immunity. These findings implicate a complex but dynamic association between mucosal permeability and immune homeostasis; however, they also emphasize that compromised gut permeability alone may not be sufficient to induce colitis. Emerging evidence further supports the role(s) of proteins associated with the mucosal barrier in epithelial injury and repair: manipulations of associated proteins also modified epithelial differentiation, proliferation, and apoptosis. Taken together, the role of gut permeability and proteins associated in regulating mucosal inflammatory diseases appears to be more complex than previously thought. Herein, we review outcomes from recent mouse models where gut permeability was altered by direct and indirect effects of manipulating mucosal barrier-associated proteins, to highlight the significance of mucosal permeability and the non-barrier-related roles of these proteins in regulating chronic mucosal inflammatory conditions.


Neural network approaches to dynamic collision-free trajectory generation.
In this paper, dynamic collision-free trajectory generation in a nonstationary environment is studied using biologically inspired neural network approaches. The proposed neural network is topologically organized, where the dynamics of each neuron is characterized by a shunting equation or an additive equation. The state space of the neural network can be either the Cartesian workspace or the joint space of multi-joint robot manipulators. There are only local lateral connections among neurons. The real-time optimal trajectory is generated through the dynamic activity landscape of the neural network without explicitly searching over the free space nor the collision paths, without explicitly optimizing any global cost functions, without any prior knowledge of the dynamic environment, and without any learning procedures. Therefore the model algorithm is computationally efficient. The stability of the neural network system is guaranteed by the existence of a Lyapunov function candidate. In addition, this model is not very sensitive to the model parameters. Several model variations are presented and the differences are discussed. As examples, the proposed models are applied to generate collision-free trajectories for a mobile robot to solve a maze-type of problem, to avoid concave U-shaped obstacles, to track a moving target and at the same to avoid varying obstacles, and to generate a trajectory for a two-link planar robot with two targets. The effectiveness and efficiency of the proposed approaches are demonstrated through simulation and comparison studies.


Using respondent-driven sampling methodology for HIV biological and behavioral surveillance in international settings: a systematic review.
To determine operational and analytical characteristics of respondent-driven sampling (RDS) in international settings and to explore factors that may affect recruitment of most-at-risk populations using RDS, we reviewed HIV biological and behavioral surveillance studies that used this method outside of the United States. We identified 123 eligible studies, 59 from Europe, 40 from Asia and the Pacific, 14 from Latin America, seven from Africa and three from Oceania. Studies collectively recruited 32,298 participants between 2003 and 2007; 53% of studies were conducted among injecting drug users, which generally had faster recruitment compared with studies among sex workers. All but 13 studies reached > or = 90% of their intended sample size, and six studies failed to reach equilibrium for key variables. This review has shown that RDS is an effective technique, when designed and implemented appropriately, to sample most-at-risk populations for HIV biological and behavioral surveys.


[Seven years of experience in patients with pulmonary arterial hypertension in Ege University Hospital: diagnostic approach of a single center].
Pulmonary arterial hypertension (PAH) is a term used to define a variety of progressive conditions that have in common, increased pulmonary vascular resistance leading to right heart failure and death. There has been considerable decrease in mortality and morbidity with the advances in PAH treatment over the past decade. However, since there is no epidemiologic study in Turkey, the prevalence of PAH and its importance is not known yet. This study aimed to evaluate the diagnostic clinical experience of Ege University Medical School Cardiology Department with PAH patients. We evaluated the diagnostic approach to patients referred to our department with the diagnosis of PAH since 2000 by retrospective analysis method. The diagnosis of pulmonary hypertension was definite in 70 patients (mean age 47+/-16 years, 61% women). Etiology from most prevalent to least was as following: congenital heart diseases (27%), chronic thromboembolic pulmonary hypertension (24%), connective tissue diseases-scleroderma (14%), idiopathic PAH (8%), diastolic dysfunction (3%), pulmonary disease (3%), pulmonary veno-occlusive disease (2%), hepatopulmonary hypertension (1%), and HIV-infection associated PAH (1%). At diagnosis, 68% of patients were in NYHA functional class-III or IV. Six-minute walk test was 263+/-127 m. Mean pulmonary artery pressure was 65+/-20 mmHg. The prognostic marker pro-BNP (brain natriuretic peptide) level was 3208+/-4145 pg/ml. Our practice shows that PAH is diagnosed late in the course of the disease in Turkey. This can be overcome with structured management in designated centers with multidisciplinary team-working in a shared care approach. There is also an urgent need for an epidemiological registry in order to determine the burden of PAH in Turkey and increase the awareness of doctors.


Fertilization effects on mean stomatal conductance are mediated through changes in the hydraulic attributes of mature Norway spruce trees.
Stomatal conductance was quantified with sap flux sensors and whole-tree chambers in mature Norway spruce (Picea abies (L.) Karst.) trees after 3 years of exposure to elevated CO(2) concentration ([CO(2)]) in a 13-year nutrient optimization experiment. The long-term nutrient optimization treatment increased tree height by 3.7 m (67%) and basal diameter by 8 cm (68%); the short-term elevated [CO(2)] exposure had no effect on tree size or allometry. Nighttime transpiration was estimated as approximately 7% of daily transpiration in unchambered trees; accounting for the effect of nighttime flux on the processing of sap flux signals increased estimated daily water uptake by approximately 30%. Crown averaged stomatal conductance (g(s)) was described by a Jarvis-type model. The addition of a stomatal response time constant (tau) and total capacitance of stored water (C(tot)) improved the fit of the model. Model estimates for C(tot) scaled with sapwood volume of the bole in fertilized trees. Hydraulic support-defined as a lumped variable of leaf-specific hydraulic conductivity and water potential gradient (K(l)DeltaPsi) -was estimated from height, sapwood-to-leaf area ratio (A(s):A(l)) and changes in tracheid dimensions. Hydraulic support explained 55% of the variation in g(s) at reference conditions for trees across nutrient and [CO(2)] treatments. Removal of approximately 50% of A(l) from three trees yielded results suggesting that stomatal compensation (i.e., an increase in g(s)) after pruning scales inversely with K(l)DeltaPsi, indicating that the higher the potential hydraulic support after pruning, the less complete the stomatal compensation for the increase in A(s):A(l).


X-ray imaging: a generalized approach using phase-space tomography.
We discuss the role of coherence in x-ray imaging and consider how phase-space tomography can be used to extract information about partial coherence. We describe the application of phase-space tomography to x-ray imaging and recover the spatial coherence properties of a one-dimensional soft (1.5 keV) x-ray beam from a synchrotron undulator source. We present phase-space information from a Young's experiment and observe negative regions in the quasi-probability distribution. We show that, given knowledge of the coherence of the beam, we can use partially coherent diffraction data to recover fully coherent information, and we present some simple experimental demonstrations of this capability.


Passive Facebook usage undermines affective well-being: Experimental and longitudinal evidence.
Prior research indicates that Facebook usage predicts declines in subjective well-being over time. How does this come about? We examined this issue in 2 studies using experimental and field methods. In Study 1, cueing people in the laboratory to use Facebook passively (rather than actively) led to declines in affective well-being over time. Study 2 replicated these findings in the field using experience-sampling techniques. It also demonstrated how passive Facebook usage leads to declines in affective well-being: by increasing envy. Critically, the relationship between passive Facebook usage and changes in affective well-being remained significant when controlling for active Facebook use, non-Facebook online social network usage, and direct social interactions, highlighting the specificity of this result. These findings demonstrate that passive Facebook usage undermines affective well-being.


New Approach to 3D Printing of Facial Prostheses Using Combination of Open Source Software and Conventional Techniques: A Case Report.
The wax sculpting of a maxillofacial prosthesis is challenging, time-consuming, and requires great skill. Rapid prototyping (RP) systems allow these hurdles to be overcome by enabling the creation of a customized 3D model of the desired prosthesis. Geomagic and Mimics are the most suitable software programs with which to design such prostheses. However, due to the high cost of these applications and the special training required to operate them, they are not widely used. Additionally, ill-fitting margins and other discrepancies in the final finished products of RP systems are also inevitable. Therefore, this process makes further treatment planning difficult for the maxillofacial prosthodontist. Here, we report the case of a 62-year-old woman who attended our clinic. Initially, she had presented with a right facial defect. This was later diagnosed as a squamous cell carcinoma and resected. The aim of this report is to describe a new technique for the 3D printing of facial prostheses which involves the combined use of open-source software, an RP system, and conventional methods of fabrication. The 3D design obtained was used to fabricate a maxillofacial prosthesis to restore the defect. The patient was happy with the esthetic outcome. This approach is relatively easy and cheap, does not require a high degree of non-medical training, and is beneficial in terms of clinical outcome.


Novel Strategies for Endothelial Preservation in Lung Transplant Ischemia-Reperfusion Injury.
Lung ischemia reperfusion (IR) injury inevitably occurs during lung transplantation. The pulmonary endothelium is the primary target of IR injury that potentially results in severe pulmonary dysfunction. Over the last decades, various molecules, receptors, and signaling pathways were identified in order to develop treatment strategies for the preservation of the pulmonary endothelium against IR injury. We here review the latest and most promising therapeutic strategies for the protection of the endothelium against IR injury. These include the stabilization of the endothelial glycocalyx, inhibition of endothelial autophagy, inhibition of adhesion molecules, targeting of angiotensin-converting enzyme, and traditional viral and novel non-viral gene transfer approaches. Though some of these strategies proved to be promising in experimental studies, very few of these treatment concepts made the transfer into clinical application. This dilemma underscores the need for more experimental evidence for the translation into clinical studies to invent therapeutic concepts against IR injury-mediated endothelial damage.


Leukemia stemness and co-occurring mutations drive resistance to IDH inhibitors in acute myeloid leukemia.
Allosteric inhibitors of mutant IDH1 or IDH2 induce terminal differentiation of the mutant leukemic blasts and provide durable clinical responses in approximately 40% of acute myeloid leukemia (AML) patients with the mutations. However, primary resistance and acquired resistance to the drugs are major clinical issues. To understand the molecular underpinnings of clinical resistance to IDH inhibitors (IDHi), we perform multipronged genomic analyses (DNA sequencing, RNA sequencing and cytosine methylation profiling) in longitudinally collected specimens from 60 IDH1- or IDH2-mutant AML patients treated with the inhibitors. The analysis reveals that leukemia stemness is a major driver of primary resistance to IDHi, whereas selection of mutations in RUNX1/CEBPA or RAS-RTK pathway genes is the main driver of acquired resistance to IDHi, along with BCOR, homologous IDH gene, and TET2. These data suggest that targeting stemness and certain high-risk co-occurring mutations may overcome resistance to IDHi in AML.


Scanning electron-microscopical and other observations of sperm fertilization reactions in Limulus polyphemus L. (Merostomata: Xiphosura).
Sperm fertilization reactions of Limulus polyphemus were examined by scanning electron and/or light microscopy. The following were considered: sperm motility, attachment of sperm to egg, acrosome reaction, and penetration of the acrosomal filament. The spermatozoa after semination are non-motile and become active only in close proximity to a defined region surrounding the egg. Egg materials diffusing into this region induce sperm motility and stimulate large numbers of spermatozoa to move towards the egg surface. Each sperm initially attaches by the apical tip and undergoes the acrosome reaction which causes a more permanent secondary attachment by the adhesion of acrosomal contents to the egg surface. The acrosome reaction also initiates the penetration of the acrosomal filament through the egg envelope, an event occurring in 70-80% of the attached spermatozoa (about 10(6). Shortly after this penetration, a secondary reaction occurs which involves a spiralling of the flagellum and an incorporation into the sperm body of the flagellar fibrous components, which then become closely apposed to the sperm nucleus. These sperm fertilization reactions were performed or initiated with 0-34 M CaCl2 in whole eggs, egg sections, excised egg envelopes and/or the outer basement lamina of the egg envelope. The Limulus fertilization system is very valuable since sperm reactions can be examined biochemically, which may lead to a better understanding of the chemical mechanisms involved in sperm-egg interactions in all animal species.


Neurolymphomatosis.
The term "neurolymphomatosis" (NL) has included infiltration of the peripheral nervous system by lymphoma and nontumor lymphocytes. We describe NL as a lymphoma entity that affects cranial and peripheral nerves and roots. We reviewed the medical records of patients at the Massachusetts General Hospital (MGH) who registered between 1972 and 2000, as well as cases published in the English-language literature. Inclusion criteria were (A) histopathologic demonstration of lymphoma within peripheral nerve, nerve root/plexus, or cranial nerve or (B) CT/MRI or intraoperative evidence of nerve enlargement and/or enhancement beyond the dural sleeve in the setting of prior or concurrent lymphoma in systemic or CNS sites. We identified 25 patients with NL in addition to 47 reported by others. Four clinical presentations were (1) painful involvement of nerves or roots, (2) cranial neuropathy with or without pain, (3) painless involvement of peripheral nerves, (4) painful or painless involvement of a single peripheral nerve. Twenty of our patients and 44 of those reported had histopathologic confirmation of lymphoma infiltrating root or nerve. In the remainder, diagnosis was based upon clinical presentation, nodular nerve enlargement or enhancement, and lymphoma cells in spinal fluid or extraneural sites. For antemortem diagnosis, imaging studies were of greatest utility, followed by biopsy. Thirty-three patients of the combined series were not correctly diagnosed until postmortem examination. Systemic chemotherapy was used to address the multiple potential sites of involvement. When properly treated, NL carries a prognosis similar to primary CNS lymphoma in the modern era.


Local and chronic application of PTH accelerates tooth movement in rats.
We previously reported that whereas systemic continuous infusion of parathyroid hormone (PTH) accelerated orthodontic tooth movement, systemic but intermittent injection of PTH did not increase the rate of tooth movement. Analysis of these data suggested that continuous administration of PTH could be applicable for orthodontic therapy. In the present study, we investigated whether local and chronic application of PTH(1-34) would accelerate orthodontic tooth movement. To increase the residence time of PTH in the injected area, we used methylcellulose (MC) gel (2% W/V) for a slow-release formulation of PTH. MC gel containing PTH (PTH-MC) continuously released biologically active PTH into the acceptor medium for more than 72 hrs in vitro. When male rats received a local injection of PTH-MC into the subperiosteum in the mesio-palatal region of the maxillary first molar (M1) every other day, M1 movement, which was mesially drawn by an orthodontic coil spring attached to the maxillary incisors, was accelerated in a dose-dependent manner. PTH-MC injection at 1 microg/400 g body weight caused a 1.6-fold increase in the rate of tooth movement. The acceleration of tooth movement by PTH-MC injection was marked on days 6, 9, and 12. Local injection of PTH dissolved in saline without MC did not significantly accelerate tooth movement on day 6 or later. Histological examination revealed active osteoclastic bone resorption and a widened periodontal space on the compression side of the periodontal tissue in the PTH-MC-injected rats. These results suggest that local injection of PTH in a slow-release formulation is applicable to orthodontic therapy.


Satellog: a database for the identification and prioritization of satellite repeats in disease association studies.
To date, 35 human diseases, some of which also exhibit anticipation, have been associated with unstable repeats. Anticipation has been reported in a number of diseases in which repeat expansion may have a role in etiology. Despite the growing importance of unstable repeats in disease, currently no resource exists for the prioritization of repeats. Here we present Satellog, a database that catalogs all pure 1-16 repeat unit satellite repeats in the human genome along with supplementary data. Satellog analyzes each pure repeat in UniGene clusters for evidence of repeat polymorphism. A total of 5,546 such repeats were identified, providing the first indication of many novel polymorphic sites in the genome. Overall, polymorphic repeats were over-represented within 3'-UTR sequence relative to 5'-UTR and coding sequence. Interestingly, we observed that repeat polymorphism within coding sequence is restricted to trinucleotide repeats whereas UTR sequence tolerated a wider range of repeat period polymorphisms. For each pure repeat we also calculate its repeat length percentile rank, its location either within or adjacent to EnsEMBL genes, and its expression profile in normal tissues according to the GeneNote database. Satellog provides the ability to dynamically prioritize repeats based on any of their characteristics (i.e. repeat unit, class, period, length, repeat length percentile rank, genomic co-ordinates), polymorphism profile within UniGene, proximity to or presence within gene regions (i.e. cds, UTR, 15 kb upstream etc.), metadata of the genes they are detected within and gene expression profiles within normal human tissues. Unstable repeats associated with 31 diseases were analyzed in Satellog to evaluate their common repeat properties. The utility of Satellog was highlighted by prioritizing repeats for Huntington's disease and schizophrenia. Satellog is available online at http://satellog.bcgsc.ca.


Cough elixir overdose causing toxic leuco-encephalopathy and serotonin syndrome.
Acute toxic leukoencephalopathy and serotonin syndrome are rare neurological complications associated with various drugs and toxins, some of which overlap. However, the co-occurrence of these conditions is poorly documented. We present the case of a 14-year-old boy who suddenly developed altered consciousness and autonomic dysfunction after consuming excessive quantities of cough remedies containing dextromethorphan, chlorphenamine, dichlorobenzyl alcohol, and amylmetacreson. Magnetic resonance imaging of the brain revealed distinct white matter lesions. With supportive care, the patient rapidly improved, and the magnetic resonance imaging abnormalities disappeared. The swift resolution, typical magnetic resonance imaging findings, and a history of exposure to drugs affecting the central nervous system's serotonergic system suggested concurrent acute toxic leukoencephalopathy and serotonin syndrome. The components of cough medications can be hazardous in overdose due to their potential to enhance serotonin toxicity and cause direct or indirect central nervous system white matter damage. Early recognition and appropriate treatment are essential for recovery.


Hepatocellular carcinoma and hepatitis virus.
Integrated hepatitis B virus (HBV) DNA is present in many hepatocellular carcinomas (HCC), suggesting that HBV has a direct oncogenic effect through interaction with transformation-associated genes. Many genes involved in cell cycle regulation (cyclins, kinases, negative regulators, Wnt-beta-catenin) and the transcriptome profile are deregulated or altered in most HCC patients. The HBx protein, potentially oncogenic via multistep carcinogenesis, modifies apoptosis, inhibits nucleotide excision and repair of damaged cellular DNA, and modulates transcriptional activation of cellular growth regulating genes. Hepatocyte transformation may be indirectly influenced by HBV DNA integration, by the generation of mutagenic oxygen reactive species, or by acquisition of mutations in association with necroinflammatory disease. HBV replication, which may occur in HCC, affects the long-term survival of patients. Prevention of HBV infection is expected to decrease the incidence of endemic HCC.


Local Disparities in Breastfeeding Initiation and Duration: A Cross-Sectional Population-Based Survey in Ten Chicago Community Areas.
Breastfeeding confers substantial health benefits to women and infants. While disparities in breastfeeding persist in the United States, the extent of these disparities at the local level is unclear. This study aimed to identify local level and racial/ethnic breastfeeding disparities within Chicago. A community-based representative survey including questions on breastfeeding was conducted in Chicago. We estimated the proportion of women who breastfed their last child for any length of time and who breastfed at 6 months by neighborhood and maternal characteristics. We performed Rao-Scott corrected chi-squared tests to analyze factors hypothesized to be associated with breastfeeding. Between March 2015 and September 2016, 641 women with at least one live birth completed the survey. We found no differences by community area in the breastfeeding initiation or breastfeeding for at least 6 months. Puerto Rican women had the lowest prevalence of breastfeeding initiation and continuation at 6 months in contrast to Mexican women who reported the highest prevalence of these practices. We found breastfeeding disparities between Puerto Rican and Mexican Hispanic subgroups. Policies and programs aimed at increasing breastfeeding should prioritize groups that are least likely to initiate breastfeeding or most likely to breastfeed for a limited duration.


Outcomes and Direct Costs of Needle Aponeurotomy, Collagenase Injection, and Fasciectomy in the Treatment of Dupuytren Contracture.
The aims of our study were to evaluate the rates and predictors of reinterventions and direct costs of 3 common treatments of Dupuytren contractures-needle aponeurotomy, collagenase injection, and surgical fasciectomy. A retrospective review identified 848 interventions for Dupuytren contracture in 350 patients treated by a single surgeon from 2005 to 2016. The treatments included needle aponeurotomy (NA) (n = 444), collagenase injection (n = 272), and open fasciectomy (n = 132). We collected information on demographics, contracture details, and comorbidities. Outcomes included reintervention rates, time to reintervention, and direct cost of treatments. Standardized costs were calculated by applying 2017 Medicare reimbursement to professional services and cost-to-charge ratios to hospital charges. Demographics were similar among the 3 treatment groups. The fifth finger was the most commonly affected digit including 43% of the NA, 60% of the collagenase, and 45% of the fasciectomy groups. The 2-year rates of reintervention following NA, collagenase, and fasciectomy were 24%, 41%, and 4%, respectively, and the 5-year rates were 61%, 55%, and 4%, respectively. Younger age and severity of preintervention proximal interphalangeal (PIP) joint contracture were predictive of reintervention in the NA and collagenase groups. The standardized direct costs for NA, collagenase, and fasciectomy were $624, $4,189, and $5,291, respectively. Including all reinterventions, the cumulative costs per digit following NA, collagenase, and surgery at 5 years were $1,540, $5,952, and $5,507, respectively. Treatment with collagenase resulted in the highest rate of reintervention at 2 years, comparable reintervention rates to NA at 5 years, and the highest cumulative costs. The NA was the least expensive and resulted in longer duration before reintervention compared with collagenase. More severe PIP joint contractures and younger age at time of initial intervention were predictive of reintervention after collagenase and NA. Fasciectomy has a high initial cost but the lowest reintervention rate. Therapeutic IV.


Time between collection and storage significantly influences bacterial sequence composition in sputum samples from cystic fibrosis respiratory infections.
Spontaneously expectorated sputum is traditionally used as the sampling method for the investigation of lower airway infections. While guidelines exist for the handling of these samples for culture-based diagnostic microbiology, there is no comparable consensus on their handling prior to culture-independent analysis. The increasing incorporation of culture-independent approaches in diagnostic microbiology means that it is of critical importance to assess potential biases. The aim of this study was to assess the impact of delayed freezing on culture-independent microbiological analyses and to identify acceptable parameters for sample handling. Sputum samples from eight adult cystic fibrosis (CF) patients were collected and aliquoted into sterile Bijou bottles. Aliquots were stored at room temperature before being frozen at -80 °C for increasing intervals, up to a 72-h period. Samples were treated with propidium monoazide to distinguish live from dead cells prior to DNA extraction, and 16S rRNA gene pyrosequencing was used to characterize their bacterial compositions. Substantial variation was observed in samples with high-diversity bacterial communities over time, whereas little variation was observed in low-diversity communities dominated by recognized CF pathogens, regardless of time to freezing. Partitioning into common and rare species demonstrated that the rare species drove changes in similarity. The percentage abundance of anaerobes over the study significantly decreased after 12 h at room temperature (P = 0.008). Failure to stabilize samples at -80 °C within 12 h of collection results in significant changes in the detected community composition.


The drag of photons by electric current in quantum wells.
The flow of electric current in quantum well breaks the space inversion symmetry, which leads to the dependence of the radiation transmission on the relative orientation of current and photon wave vector, this phenomenon can be named current drag of photons. We have developed a microscopic theory of such an effect for intersubband transitions in quantum wells taking into account both depolarization and exchange-correlation effects. It is shown that the effect of the current drag of photons originates from the asymmetry of intersubband optical transitions due to the redistribution of electrons in momentum space. We show that the presence of dc electric current leads to the shift of intersubband resonance position and affects both transmission coefficient and absorbance in quantum wells.


Betagamma subunits of pertussis toxin-sensitive G proteins mediate A1 adenosine receptor agonist-induced activation of phospholipase C in collaboration with thyrotropin. A novel stimulatory mechanism through the cross-talk of two types of receptors.
COS-7 cells were transiently transfected with human thyrotropin receptor and dog A1 adenosine receptor cDNAs. An A1 agonist, N6-(L-2-phenylisopropyl) adenosine (PIA), which is ineffective alone, enhanced the thyrotropin (TSH)-induced inositol phosphate production, reflecting phospholipase C (PLC) activation, but inhibited the TSH-induced cAMP accumulation, reflecting adenylyl cyclase inhibition. These PIA-induced actions were completely inhibited by pertussis toxin (PTX) treatment. Moreover, in the cells expressing a PTX-insensitive mutant of Gi2alpha or Gi3alpha, in which a glycine residue was substituted for a cysteine residue to be ADP-ribosylated by PTX, at the fourth position of the C terminus, PIA effectively exerted both stimulatory and inhibitory effects on the TSH-induced actions although the cells were treated with the toxin. Overexpression of the betagamma subunits of the G proteins enhanced the TSH-induced inositol phosphate production without any significant effect on the cAMP response; under these conditions, PIA did not further increase the elevated inositol phosphate response to TSH. On the contrary, overexpression of a constitutively active mutant of Gi2alpha, in which the guanosine triphosphatase activity is lost, inhibited the TSH-induced cAMP accumulation but hardly affected the inositol phosphate response; under these conditions, PIA never exerted further inhibitory effects on the cAMP response to TSH. In contrast to the case of the TSH-induced inositol phosphate response, the response to a constitutively active G11alpha mutant was not appreciably affected, and that to NaF was rather inhibited by PIA and overexpression of the betagamma subunits. Taken together, these results suggest that a single type of PTX-sensitive G protein mediates the A1 adenosine receptor-linked modulation of two signaling pathways in collaboration with an activated thyrotropin receptor; alpha subunits of the PTX-sensitive G proteins mediate the inhibitory action on adenylyl cyclase, and the betagamma subunits mediate the stimulatory action on PLC. In the case of the latter stimulatory action on PLC, the betagamma subunits may not directly activate PLC. The possible mechanism by which betagamma subunits enhance the TSH-induced PLC activation is discussed.


Osteoblastic proliferation in bone biopsies from patients with end-stage chronic renal failure.
Osteoblasts have traditionally been considered to be terminally differentiated cells and therefore unable to divide. Data in recent years, however, indicate that cellular differentiation does not usually preclude preservation of proliferative ability and that most differentiated cells are able to divide under adequate stimuli. The aim of this study was to assess whether cubic osteoblasts undergo proliferation during the formation phase of the remodeling cycle under a stimulus that increased bone turnover. For that purpose, the osteoblastic proliferation index (OPI) was analyzed by DNA image cytometry in transiliac bone biopsies from 33 patients with chronic renal failure (23 men, 10 women; mean age 50.4 +/- 15.1 years) who have been classified into low (n = 13), normal (n = 15), and high (n = 15) bone turnover according to activation frequency (Ac.f). OPI was significantly higher (p < 0.002) in the high bone turnover group (13.90 +/- 4.72%) compared with the low (2.38 +/- 4.13%) and normal turnover groups (2.84 +/- 4.04%). There was a positive correlation between OPI and the following histomorphometric parameters: bone formation rate, surface referent (r = 0.76, p = 0.00001), activation frequency (r = 0.73, p = 0.00001), mineral apposition rate (r = 0.73, p = 0.00001), bone formation rate, volume referent (r = 0.71, p = 0.00001), and mineralizing surface (r = 0.62, p = 0.0001). This study shows that a rise in bone turnover is associated with a marked increase of bone-forming cell proliferation in patients with end-stage chronic renal failure. From this finding, it may be concluded that cubic osteoblasts do not behave as "terminally differentiated" cells in vivo, because a high proportion of them are still able to divide.


[Changes in the functional activity of neutrophils during their interaction with Yersinia pestis in vitro].
The functional state and electrochemical properties of human blood neutrophil leukocytes after their in vitro interaction with Y. pestis cells, strain EV, was analyzed. A considerable decrease in the electrophoretic mobility of neutrophil leukocytes and a considerable increase in their phagocytic indices was shown. At the same time the maximum phagocytic activity in the total pool of isolated neutrophil leukocytes was registered in fractions having higher electrophoretic mobility. The dependence of electrophoretic mobility on the state of neutrophil membranes, as well as the degree of their activation, is discussed.


Hyperthermophilic enzymes: sources, uses, and molecular mechanisms for thermostability.
Enzymes synthesized by hyperthermophiles (bacteria and archaea with optimal growth temperatures of > 80 degrees C), also called hyperthermophilic enzymes, are typically thermostable (i.e., resistant to irreversible inactivation at high temperatures) and are optimally active at high temperatures. These enzymes share the same catalytic mechanisms with their mesophilic counterparts. When cloned and expressed in mesophilic hosts, hyperthermophilic enzymes usually retain their thermal properties, indicating that these properties are genetically encoded. Sequence alignments, amino acid content comparisons, crystal structure comparisons, and mutagenesis experiments indicate that hyperthermophilic enzymes are, indeed, very similar to their mesophilic homologues. No single mechanism is responsible for the remarkable stability of hyperthermophilic enzymes. Increased thermostability must be found, instead, in a small number of highly specific alterations that often do not obey any obvious traffic rules. After briefly discussing the diversity of hyperthermophilic organisms, this review concentrates on the remarkable thermostability of their enzymes. The biochemical and molecular properties of hyperthermophilic enzymes are described. Mechanisms responsible for protein inactivation are reviewed. The molecular mechanisms involved in protein thermostabilization are discussed, including ion pairs, hydrogen bonds, hydrophobic interactions, disulfide bridges, packing, decrease of the entropy of unfolding, and intersubunit interactions. Finally, current uses and potential applications of thermophilic and hyperthermophilic enzymes as research reagents and as catalysts for industrial processes are described.


Inhibition of vitamin d receptor translocation by cigarette smoking extracts.
Vitamin D can translocate a vitamin D receptor (VDR) from the nucleus to the cell membranes. The meaning of this translocation is not elucidated in terms of a role in pathogenesis of chronic obstructive pulmonary disease (COPD) till now. VDR deficient mice are prone to develop emphysema, suggesting that abnormal function of VDR might influence a generation of COPD. The blood levels of vitamin D have known to be well correlated with that of lung function in patients with COPD, and smoking is the most important risk factor in development of COPD. This study was performed to investigate whether cigarette smoke extracts (CSE) can inhibit the translocation of VDR and whether mitogen activated protein kinases (MAPKs) are involved in this inhibition. Human alveolar basal epithelial cell line (A549) was used in this study. 1,25-(OH(2))D(3) and/or MAPKs inhibitors and antioxidants were pre-incubated before stimulation with 10% CSE, and then nucleus and microsomal proteins were extracted for a Western blot of VDR. Five minutes treatment of 1,25-(OH(2))D(3) induced translocation of VDR from nucleus to microsomes by a dose-dependent manner. CSE inhibited 1,25-(OH(2))D(3)-induced translocation of VDR in both concentrations of 10% and 20%. All MAPKs inhibitors did not suppress the inhibitory effects of CSE on the 1,25-(OH(2))D(3)-induced translocation of VDR. Quercetin suppressed the inhibitory effects of CSE on the 1,25-(OH(2))D(3)-induced translocation of VDR, but not in n-acetylcysteine. CSE has an ability to inhibit vitamin D-induced VDR translocation, but MAPKs are not involved in this inhibition.


[Phloretin induces apoptosis of BEL-7402 cells in vitro].
To examine the effect of phloretin on apoptosis of BEL-7402 cells. The viability changes of BEL- 7402 cells as a result of phloretin-induced toxicity were analyzed using MTT assay, and the cell morphology changes were observed with fluorescence microscope. Flow cytometry was used to analyze the cell cycle and mitochondrial membrane potential changes, and chromogenic substrate assay performed to detect caspase activity. Phloretin induced obvious cytotoxicity against BEL-7402 cells with IC50 of 89.23 microg/mL. The growth curve demonstrated decreased growth of the cells as phloretin concentration increased. Cell apoptosis occurred 24 h after treatment with 40-160 microg/mL phloretin. Morphological, the cells exposed to phloretin exhibited nuclear chromatin condensation and increased fluorescence intensity. The activity of caspase-9 reached the peak level 12 h after phloretin exposure, and leak levels of caspase-6 and caspase-3 activities occurred 18 and 24 h after the exposure, respectively. Phloretin can induce BEL-7402 cell apoptosis though the mitochondrial pathway.


Synthesis of imidazole derivatives and study of the ON-based different memory performances.
We report the synthesis of two imidazole-based small molecules with different planarity of terminal aromatic rings and their application in memory devices with a sandwich configuration. The optical, electric, and the on-based device performances were systematically investigated. Surprisingly, the device based on BT-PMZ exhibited volatile static random access memory (SRAM) behavior, whereas that based on BT-BMZ showed nonvolatile write-once-read-many-times (WORM) behavior. Further studies on the film morphology and the molecular electronic structure were carried out to investigate the underlying mechanism for the large difference in their performance. Moreover, the performance of the device that incorporates a LiF buffer layer (5 nm) embedded at the interface between the BT-BMZ active layer and the Al top electrode as well as that of the device with a cold-deposited top electrode of mercury droplet was further investigated. At that point a dramatic change in memory performance of the devices from the WORM to SRAM type was observed. The intrinsic volatile SRAM performance for the two molecules results from the moderate electron-withdrawing strength of the acceptor moieties and thus weak trapping of the charge carriers.


Trust, mistrust, racial identity and patient satisfaction in urban African American primary care patients of nurse practitioners.
To analyze relationships between cultural mistrust, medical mistrust, and racial identity and to predict patient satisfaction among African American adults who are cared for by primary-care nurse practitioners using Cox's Interaction Model of Client Health Behaviors. A descriptive-correlational study was conducted with a convenience sample of 100 community-dwelling adults. Participants completed the Cultural Mistrust Inventory; Group Based Medical Mistrust Scale; Black Racial Identity Attitude Scale; Trust in Physician Scale; Michigan Academic Consortium Patient Satisfaction Questionnaire; and provided demographic and primary care data. Correlations and stepwise multiple regression techniques were used to examine the study aims and correlational links between the theoretical constructs of client singularity, client-professional interaction, and outcome. Cox's model indicated a complex view of African American patients' perspectives on nurse practitioners. Participants simultaneously held moderate cultural mistrust of European American providers and mistrust of the health care system, and high levels of trust and satisfaction with their nurse practitioners. One racial identity schema (conformity) and trust of nurse-practitioner (NP) providers explained 41% of variance in satisfaction. An African American patient's own attitudes about racial identity and the client-professional relationship have a significant effect on satisfaction with primary care.


Is there a link between glucose levels and heart failure? An update.
It has been well documented that there is an increased prevalence of standard cardiovascular (CV) risk factors in association with diabetes and with diabetes-related abnormalities. Hyperglycemia, in particular, also plays an important role. Heart failure (HF) has become a frequent manifestation of cardiovascular disease (CVD) among individuals with diabetes mellitus. Epidemiological studies suggest that the effect of hyperglycemia on HF risk is independent of other known risk factors. Analysis of datasets from populations including individuals with dysglycemia suggests the pathogenic role of hyperglycemia on left ventricular function and on the natural history of HF. Despite substantial epidemiological evidence of the relationship between diabetes and HF, data from available interventional trials assessing the effect of a glucose-lowering strategy on CV outcomes are limited. To provide some insight into these issues, we describe in this review the recent important data to understand the natural course of CV disease in diabetic individuals and the role of hyperglycemia at different times in the progression of HF.


School nurses' competence in caring for students who depend on medical technology.
This study explored the experiences of school nurses in giving care to students who depend on medical technology. From it, insight was gained into the nurses' competence in areas related to several aspects of care, ranging from planning to delegation. Six contributing factors to school nurses' competence were identified: challenge and excitement; education and experience; preparation and planning; collaboration with others; availability of expert resources; and reinforcement from successful outcomes.


[Prognostic factors and survival in adult acute leukemia in Burkina Faso].
Acute leukemia is both a diagnostic and therapeutic emergency. Our study aimed to describe the prognostic factors and survival of adults with acute leukemia in Burkina Faso. Cross-sectional descriptive study with retrospective data collection covering a period of 4.5 years (2018-2022) in two university hospitals in Burkina Faso. Were included all patients over 18 years hospitalized for acute leukemia in these sites with a usable medical record. A total of 42 cases were collected, of which 45% suffered from acute lymphoblastic leukemia and 43% from acute myeloid leukemia. In 12% of cases, acute leukemia was not classified. The average age was 35 ± 15 years, with extremes of 19 and 72 years. 12% of the patients presented an age of poor prognosis. Comorbidities were present in 14% of patients. The deterioration in general condition was fairly constant with 95% of patients at WHO stages 3 and 4. All patients presented with bone marrow failure syndrome and tumor syndrome was found in 45%. Anemia and thrombocytopenia were present in almost all cases. Hyperleukocytosis at diagnosis was present in 28 patients (67%); among them 18 patients (64%) had leukocytes greater than 50 G/L. Death in hospital was found in 38% of patients and loss of sight in 31%. The median survival was 3 months. Survival was 30% at 6 months and 0% at 12 months. Acute leukemias are in our practice conditions of poor prognosis with a fairly short survival.


Early-onset schizophrenia.
The available study findings on the course and outcome of schizophrenia beginning in childhood or adolescence can be summarized as follows. (1) Schizophrenic psychoses that arise before the age of 13 have a very poor prognosis. The disease usually continues to progress in adolescence and adulthood. It can be diagnosed with the same criteria that are used for adults. (2) Patients whose disease is of acute onset, with productive schizophrenic manifestations such as hallucinations and delusions (positive manifestations), have a better prognosis than those whose disease begins insidiously and takes an unfavorable course, with depressive states and continually worsening impairment of cognitive function. (3) The patient's premorbid personality plays a major role. Patients who were described as socially active, intelligent, and integrated children and adolescents before they became ill have a better prognosis than those who were intellectually impaired, timid, introverted and uncommunicative before they became ill. (4) The prognosis seems to be better for patients who have no family history of schizophrenia, those whose families cooperate well, and those whose condition improves rapidly during inpatient treatment. (5) The few available studies on the course and outcome of schizophrenia beginning in childhood and early adolescence confirm that they are much worse than in adult-onset schizophrenia. (6) A 42-year longitudinal study of patients with childhood-onset schizophrenia revealed their suicide rate to be higher than that of patients with adult-onset schizophrenia. No further longitudinal studies are available to confirm this finding.


Equine basal cell tumors: 6 cases (1985-1999).
Basal cell tumors are rare benign tumors in horses. Over a 15-year period, 6 horses were diagnosed with basal cell tumors. The tumors were well-circumscribed. freely moveable, firm, raised papules, nodules, or masses that ranged from 0.6 to 5 cm in diameter. Five of the 6 tumors were ulcerated. Based on gross appearance, the tumors were diagnosed as sarcoids, and 1 was diagnosed as a melanoma. The range of age of affected horses was 6-26 years. The tumors were identified clinically 1 week to 3 years before excision. In 4 horses for which information was available, complete surgical excision was curative with no recurrence 4 months to 2 years after removal.


Lipoprotein(a) levels and apolipoprotein(a) polymorphism in type 1 diabetes mellitus: relationships to microvascular and neurological complications.
To investigate plasma concentrations of lipoprotein(a) [Lp(a)] and apolipoprotein(a) [apo(a)] polymorphism in relation to the presence of microvascular and neurological complications in type 1 diabetes mellitus, 118 young diabetic patients and 127 age-matched controls were recruited. Lp(a) levels were higher in patients than in controls, but the apo(a) isoforms distribution did not differ between the two groups [higher prevalence of isoforms of high relative molecular mass (RMM) in both groups]. Microalbuminuric patients had Lp(a) levels significantly greater than normoalbuminuric patients, and normoalbuminuric patients showed higher Lp(a) levels than controls. Patients with retinopathy or neuropathy showed similar Lp(a) levels to those without retinopathy or neuropathy. No differences in apo(a) isoforms frequencies were observed between subgroups with and without complications (higher prevalence of isoforms of high RMM in every subgroup). However, among patients with retinopathy, those with proliferative retinopathy had higher Lp(a) levels and a different apo(a) isoforms distribution (higher prevalence of isoforms of low RMM) than those with non-proliferative and background retinopathy (higher prevalence of isoforms of high RMM). Our data suggest that young type 1 diabetic patients without microalbuminuria have Lp(a) levels higher than healthy subjects of the same age. Lp(a) levels are further increased in microalbuminuric patients. High Lp(a) levels and apo(a) isoforms of low RMM seem to be associated with the presence of proliferative retinopathy, but have no relation to neuropathy.


Prospective and retrospective duration memory in the hippocampus: is time in the foreground or background?
Psychologists have long distinguished between prospective and retrospective timing to highlight the difference between our sense of duration during an experience in passing and our sense of duration in hindsight. Humans and other animals use prospective timing in the seconds-to-minutes range in order to learn durations, and can organize their behaviour based upon this knowledge when they know that duration information will be important ahead of time. By contrast, when durations are estimated after the fact, thus precluding the subject from consciously attending to temporal information, duration information must be extracted from other memory representations. The accumulated evidence from prospective timing research has generally led to the hippocampus (HPC) being casted in a supporting role with prefrontal-striatal, cortical or cerebellar circuits playing the lead. Here, I review findings from the animal and human literature that have led to this conclusion and consider that the contribution of the HPC to duration memory is understated because we have little understanding about how we remember duration.


Inhibition of the heterotetrameric K+ channel KCNQ1/KCNE1 by the AMP-activated protein kinase.
The heterotetrameric K(+)-channel KCNQ1/KCNE1 is expressed in heart, skeletal muscle, liver and several epithelia including the renal proximal tubule. In the heart, it contributes to the repolarization of cardiomyocytes. The repolarization is impaired in ischemia. Ischemia stimulates the AMP-activated protein kinase (AMPK), a serine/threonine kinase, sensing energy depletion and stimulating several cellular mechanisms to enhance energy production and to limit energy utilization. AMPK has previously been shown to downregulate the epithelial Na(+) channel ENaC, an effect mediated by the ubiquitin ligase Nedd4-2. The present study explored whether AMPK regulates KCNQ1/KCNE1. To this end, cRNA encoding KCNQ1/KCNE1 was injected into Xenopus oocytes with and without additional injection of wild type AMPK (AMPKα1 + AMPKβ1 + AMPKγ1), of the constitutively active (γR70Q)AMPK (α1β1γ1(R70Q)), of the kinase dead mutant (αK45R)AMPK (α1(K45R)β1γ1), or of the ubiquitin ligase Nedd4-2. KCNQ1/KCNE1 activity was determined in two electrode voltage clamp experiments. Moreover, KCNQ1 abundance in the cell membrane was determined by immunostaining and subsequent confocal imaging. As a result, wild type and constitutively active AMPK significantly reduced KCNQ1/KCNE1-mediated currents and reduced KCNQ1 abundance in the cell membrane. Similarly, Nedd4-2 decreased KCNQ1/KCNE1-mediated currents and KCNQ1 protein abundance in the cell membrane. Activation of AMPK in isolated perfused proximal renal tubules by AICAR (10 mM) was followed by significant depolarization. In conclusion, AMPK is a potent regulator of KCNQ1/KCNE1.


Including the term 'tobacco-free nicotine' in the nicotine addiction warning label mandated by the US Food and Drug Administration alters risk perceptions and use intentions.
The US Food and Drug Administration (FDA) requires a warning label on nicotine e-cigarettes and pouches: 'This product contains nicotine. Nicotine is an addictive chemical'. Some brands marketing synthetic nicotine products have modified the warning ('This product contains tobacco-free nicotine (TFN)…'). The public health impact of altering the warning is unknown, so we examined its impact on risk perceptions and use intentions. 1000 participants completed an anonymous online survey. Participants viewed the black-and-white FDA and TFN-modified warning labels in isolation, in a randomised order and reported on perceived addictiveness and, secondarily, use intentions. Participants then selected which label conveyed the most harm overall. Generalised estimating equations (GEEs) were used to evaluate the impact of label type and participant characteristics on perceived addictiveness and, secondarily, use intentions. Multivariable logistic regression was used to evaluate relationships between participant characteristics and choosing which label conveyed the most harm. Overall, the TFN-modified label was associated with lower addictiveness ratings but not increased use intentions. Where significant interactions between label type and participant characteristics emerged, TFN-modified labelling was associated with disproportionately reduced risk perceptions or increased use intentions among vulnerable populations (eg, underage individuals, racially minoritised groups). 25.5% of participants selected the TFN-modified label as conveying the most harm, with younger individuals (<21 years) significantly less likely to choose the TFN-modified label. Modifying the FDA-mandated nicotine warning label to include 'tobacco-free nicotine' may negatively impact public health, so the FDA should enforce inclusion of its original required warning label.


Parental substance use disorder and child abuse: risk factors for child maltreatment?
Although the literature consistently shows an association between parental substance use disorders (SUDs) and child abuse, it is unknown what factors discern non-abusive and abusive parents with SUDs. This study aims to investigate which specific risk factors are associated with child abuse in clinically treated parents with SUDs in the Netherlands. It examines two groups of parents with SUDs in a clinical setting, with and without known instances of child abuse. These groups were compared on SUD-related factors such as the type and severity of the SUDs, and variables addressing psychological disability such as comorbid diagnoses and quality of life. Other than a marginally significant difference in severity of addiction and a lower mean age of the parents in the child abuse group, no significant differences were found. The small sample size and the inherent difficulty of studying SUDs in a clinical sample is likely to have affected the results.